Abstract 1332: Functional killer-immunoglobulin-like receptor variation and risk of non-melanoma skin cancer.

Abstract

Abstract Natural killer (NK) cells of the immune system are the first line of defense against transformed and infected cells. NK cell action is determined through binding of killer immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands on target cells. The KIR gene family is diverse and highly polymorphic, is poorly covered on GWAS platforms, and exhibits significant functional copy number variation. The KIR locus has been primarily studied in the context of HCV, HIV, and transplant outcomes. Here, we have tested the hypothesis that KIR genotypes are associated with Non-Melanoma Skin Cancer (NMSC) etiology. These are among the most prevalent malignancies worldwide with rising incidence. In addition, they are highly antigenic tumors, with a possible viral etiology, making NMSC an ideal model to test KIR as a cancer susceptibility trait. A random subset of a population-based case-control study in New Hampshire was selected for the study: 422 basal cell carcinomas (BCC) (1 BCC=243, 2 BCC=131, ≥3 BCC=48), 132 squamous cell carcinomas (SCC), and 222 controls. KIR genotyping was performed with Lifecodes KIR-SSO typing kit on Luminex using buffy coat derived genomic DNA, capturing KIR loci: 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 2DP1, 2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 3DL1, 3DS1, and 3DL2. Cutaneous HPV status was assessed using serum samples and established Luminex detection assays covering 16 genus beta HPV types. The KIR2DL2/3 locus was associated with a significantly increased risk of BCC (OR=2.65, 95% CI: 1.08-6.48), which was particularly strong for cases with 3 or more tumors (OR=5.77, 95% CI: 1.30-25.66). For SCC, the KIR3DL1 gene was associated with a significantly increased risk of malignancy (OR=3.73, 95% CI: 1.51-9.22). Next we investigated the association of KIR and SCC within HPV strata. The KIR3DL1-SCC association was strongest among those with no evidence of HPV infection (OR=6.81, 95% CI: 1.78-26.12). In contrast, the non-functional KIR2DS4 variant related to an increased risk and the KIR2DL2 gene related to reduced risk of SCC among those with multiple β-HPV infections. Our results implicate a strong role for KIR in the etiology of NMSC. KIR2DL2/3 may be particularly important in the development of multiple BCC, and KIR3DL1 in the pathogenesis of SCC. Finally, we identified a pattern of KIR-SCC associations that supports a potential etiologic role of cutaneous HPV in SCC occurrence. Citation Format: Karin A. Vineretsky, Margaret R. Karagas, Michael Pawlita, Heather H. Nelson. Functional killer-immunoglobulin-like receptor variation and risk of non-melanoma skin cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1332. doi:10.1158/1538-7445.AM2013-1332